Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

BACKGROUND: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: OBJECTIVES: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. DESIGN: A proof of concept double-masked randomized controlled study. PARTICIPANTS: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile. INTERVENTION: Simvastatin 40 mg/day or placebo, allocated 1:1. MAIN OUTCOME MEASURES: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. CONCLUSION/SIGNIFICANCE: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Regularity Properties and Pathologies of Position-Space Renormalization-Group Transformations

We reconsider the conceptual foundations of the renormalization-group (RG) formalism, and prove some rigorous theorems on the regularity properties and possible pathologies of the RG map. Regarding regularity, we show that the RG map, defined on a suitable space of interactions (= formal Hamiltonians), is always single-valued and Lipschitz continuous on its domain of definition. This rules out a recently proposed scenario for the RG description of first-order phase transitions. On the pathological side, we make rigorous some arguments of Griffiths, Pearce and Israel, and prove in several cases that the renormalized measure is not a Gibbs measure for any reasonable interaction. This means that the RG map is ill-defined, and that the conventional RG description of first-order phase transitions is not universally valid. For decimation or Kadanoff transformations applied to the Ising model in dimension $d \ge 3$, these pathologies occur in a full neighborhood $\{ \beta > \beta_0 ,\, |h| < \epsilon(\beta) \}$ of the low-temperature part of the first-order phase-transition surface. For block-averaging transformations applied to the Ising model in dimension $d \ge 2$, the pathologies occur at low temperatures for arbitrary magnetic-field strength. Pathologies may also occur in the critical region for Ising models in dimension $d \ge 4$. We discuss in detail the distinction between Gibbsian and non-Gibbsian measures, and give a rather complete catalogue of the known examples. Finally, we discuss the heuristic and numerical evidence on RG pathologies in the light of our rigorous theorems.Comment: 273 pages including 14 figures, Postscript, See also ftp.scri.fsu.edu:hep-lat/papers/9210/9210032.ps.

Connectivity of larval stages of sedentary marine communities between hard substrates and offshore structures in the North Sea

Man-made structures including rigs, pipelines, cables, renewable energy devices, and ship wrecks, offer hard substrate in the largely soft-sediment environment of the North Sea. These structures become colonised by sedentary organisms and non-migratory reef fish, and form local ecosystems that attract larger predators including seals, birds, and fish. It is possible that these structures form a system of interconnected reef environments through the planktonic dispersal of the pelagic stages of organisms by ocean currents. Changes to the overall arrangement of hard substrate areas through removal or addition of individual man-made structures will affect the interconnectivity and could impact on the ecosystem. Here, we assessed the connectivity of sectors with oil and gas structures, wind farms, wrecks, and natural hard substrate, using a model that simulates the drift of planktonic stages of seven organisms with sedentary adult stages associated with hard substrate, applied to the period 2001–2010. Connectivity was assessed using a classification system designed to address the function of sectors in the network. Results showed a relatively stable overall spatial distribution of sector function but with distinct variations between species and years. The results are discussed in the context of decommissioning of oil and gas infrastructure in the North Sea

Tools and Strategies to Integrate Multi-Domain Information for Personalized Decision-Making in Oncological Care Pathways: A Scoping Review

Thanee M Uittenhout,1 Jesse Jansen,1 Kon-Siong Jie,2 Lieke Welling,3 Barbara L van Leeuwen,4 Leti van Bodegom-Vos,5 Anne M Stiggelbout,5,6 Trudy van der Weijden,1 IPTO Consortium: the scientific members of the IPTO ConsortiumA. Koch, F.M. van Nuenen, H. van der Wal-Huisman, L.L. van Baalen, M.J. Nogarede, S. Festen, V.C. Hanewinkel On behalf of the IPTO Consortium1Department of Family Medicine, Care and Public Health Research Institute (CAPHRI), Faculty of Health Medicine and Life Sciences (FHML) Maastricht University, Maastricht, the Netherlands; 2Department of Internal Medicine, Zuyderland Medical Center, Sittard, the Netherlands; 3Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands; 4Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 5Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; 6Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the NetherlandsCorrespondence: Thanee M Uittenhout, Email [email protected]: There is a growing interest in personalized decision-making in oncology. According to the Integrated Oncological Decision-Making Model (IODM), decisions should be based on information from three domains: (1) medical technical information, (2) patients’ general health status and (3) patients’ preferences and goals. Little is known about what kind of tool/strategy is used to collect the information, by whom this is collected (nurse, clinician) when this is collected (moment in the care pathway), and how this information should be collected and integrated within decision-making in oncological care pathways, and what its impact is.Methods: We searched PUBMED, Embase and Web of Science in October 2023 for studies looking at tools to collect and integrate information from the three domains of the IODM. We extracted data on the content and implementation of these tools, and on decision and patient outcomes.Results: The search yielded 2576 publications, of which only seven studies described collection of information from all three domains (inclusion criteria). In the seven included studies, information on the three domains was collected through dialogue, questionnaires, and assessments (what) by a nurse (2 out of 7 studies) or by other members of the Multi-Disciplinary Team (by whom) (5 out of 7 studies). Members of the Multi-Disciplinary Team subsequently integrated the information (5 out 7 studies) during their meeting (when), with patients and family attending this meeting in 2 studies (how). In terms of decision outcomes, 5 out of 7 studies compared the treatment recommendations before and after implementation of the tools, showing a modification of the treatment plan in 3% to 53% of cases. The limited data on patient outcomes suggest positive effects on well-being and fewer complications (3 out of 7 studies).Conclusion: The seven studies identified that integrated information from the three IODM domains into treatment decision-making lacked comprehensive information regarding the strategies, process, timing and individuals involved in implementing the tools. Nevertheless, the few studies that looked at patient outcomes showed promising findings.Keywords: person centred care, patient centred care, patient preferences, treatment decision-making, multi-disciplinary team, oncolog

Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice

Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism

Combined Tevatron upper limit on gg->H->W+W- and constraints on the Higgs boson mass in fourth-generation fermion models

Report number: FERMILAB-PUB-10-125-EWe combine results from searches by the CDF and D0 collaborations for a standard model Higgs boson (H) in the process gg->H->W+W- in p=pbar collisions at the Fermilab Tevatron Collider at sqrt{s}=1.96 TeV. With 4.8 fb-1 of integrated luminosity analyzed at CDF and 5.4 fb-1 at D0, the 95% Confidence Level upper limit on \sigma(gg->H) x B(H->W+W-) is 1.75 pb at m_H=120 GeV, 0.38 pb at m_H=165 GeV, and 0.83 pb at m_H=200 GeV. Assuming the presence of a fourth sequential generation of fermions with large masses, we exclude at the 95% Confidence Level a standard-model-like Higgs boson with a mass between 131 and 204 GeV.We combine results from searches by the CDF and D0 collaborations for a standard model Higgs boson (H) in the process gg→H→W+W- in pp̅ collisions at the Fermilab Tevatron Collider at √s=1.96  TeV. With 4.8  fb-1 of integrated luminosity analyzed at CDF and 5.4  fb-1 at D0, the 95% confidence level upper limit on σ(gg→H)×B(H→W+W-) is 1.75 pb at mH=120  GeV, 0.38 pb at mH=165  GeV, and 0.83 pb at mH=200  GeV. Assuming the presence of a fourth sequential generation of fermions with large masses, we exclude at the 95% confidence level a standard-model-like Higgs boson with a mass between 131 and 204 GeV.Peer reviewe

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: The GENOMOS study (vol 3, pg 223, 2006)

Background Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. Methods and Findings Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups ( p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), ( p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. Conclusions Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases